It is sometimes desired to form a composition of amorphous drug and a polymer. One reason for forming such compositions is that the aqueous concentration of a poorly soluble drug may be improved by such a technique. For example, EP 0 901 786 A2 to Curatolo et al. discloses forming pharmaceutical spray-dryed dispersions of sparingly soluble drugs and the polymer hydroxypropyl methyl cellulose acetate succinate, in which the drug is amorphous and dispersed in the polymer. The spray-dried dispersions disclosed in Curatolo et al. provide superior aqueous concentration relative to dispersions formed from other methods and relative to the crystalline drug alone.
Similarly, others have recognized the enhancement in aqueous concentration afforded by forming compositions of a drug in a polymer. U.S. Pat. No. 5,456,923 to Nakamichi et al. discloses solid dispersions formed by twin-screw extrusion of low solubility drugs and various polymers.
Poloxamers (polyoxyethylene-polyoxypropylene copolymers) are routinely used in the pharmaceutical arts for a variety of applications, primarily as emulsifying agents in intravenous fat emulsions, and as solubilizing and stabilizing agents to maintain the clarity of elixirs and syrups. Poloxamers are also used as wetting agents; in ointments, suppository bases, and gels; and as tablet binders and coatings.
Forming compositions of poloxamers and drugs is known. U.S. Pat. No. 6,368,622 to Chen et al. discloses a mixture of drug with a poloxamer. In a particular embodiment, the drug fenofibrate, having a melting point of 72° to 82° C. and a glass transition temperature (Tg) of about −19° C., is melted with a poloxamer. While the data show the drug in the composition has a faster dissolution rate than a commercial formulation, no concentration enhancement was demonstrated.
U.S. Patent Application Publication No. US2001/0036959A1 to Gabel et al. discloses a composition comprising the drug carvedilol, having a melting point of 113° to 116° C. and a Tg of about 39° C., in a concentration above 5 wt %. The preparation preferably includes poloxamers. The composition may be formed using a melt method or by spray-drying.
European Patent Specification EP 0836475B1 to Clancy et al. discloses a solid composition of an active ingredient in a hydrophilic poloxamer polymer. The composition is formed either by melting the poloxamer and dispersing the active ingredient therein or dissolving the active ingredient and poloxamer in an organic solvent or solvents; the solvent is evaporated and the molten poloxamer is cooled and milled to obtain the formulation.
However, a problem with forming solid compositions containing amorphous drug and a substantial amount of poloxamer is that the drug can crystallize over time, leading to poor performance. Thus, there is a continuing need to provide methods and formulations for enhancing the concentration of low-solubility drugs while providing physical stability.